Genetics of Osteoporosis: Perspectives for Personalized Medicine

Wen-Feng Li; Shu-Xun Hou; Bin Yu; Dan Jin; Claude Férec; Jian-Min Chen

Personalized Medicine. 2010;7(6):655-668.

Abstract and Introduction

Abstract

Osteoporosis is the most common metabolic bone disorder worldwide. At least 15 genes (e.g., ESR1, LRP5, SOST, OPG, RANK and RANKL) have been confirmed as osteoporosis susceptibility genes, and another 30 have been highlighted as promising susceptibility genes. Notably, these genes are clustered in three biological pathways: the estrogen endocrine pathway, the Wnt/β-catenin signaling pathway and the RANK/RANKL/osteoprotegerin (OPG) pathway. In this article, using data pertaining to these three biological pathways as examples, we illustrate possible principles of personalized therapy for osteoporosis. In particular, we propose to use inhibitors (e.g., denosumab) of the RANK/RANKL/OPG signaling pathway to circumvent resistance to estrogen-replacement therapy: a novel idea resulting from the consideration of a mechanistic link between the estrogen endocrine pathway and the RANK/RANKL/OPG signaling pathway. In addition, we call for more attention to be focused on rare variants of major effects in future studies.

Introduction

Osteoporosis is characterized by compromised bone strength, and consequently, increased risk of fracture. It is the most common metabolic bone disorder worldwide; approximately 50% of women and 20% of men aged older than 50 years will experience one or more osteoporotic fractures in their remaining lifetime.^[1] In principle, osteoporosis could result from:

A failure to achieve a skeleton of optimal strength during growth and development;
Excessive bone resorption resulting in loss of bone mass and disruption of architecture;
A failure to replace lost bone due to defects in bone formation.^[2]

The risk of osteoporosis is influenced by many factors such as age, sex, diet, physical activity, medication use and menopausal status, but one of the most important clinical risk factors is a positive family history, underscoring the role of genetic factors in determining disease susceptibility.^[3] Recently, we provided a comprehensive review of advances made over the past 15 years with respect to the discovery of osteoporosis causing genes. We noted an accelerating pace in identifying and validating osteoporosis susceptibility loci in the past 4 years, which was largely attributable to the use of genome-wide association studies (GWASs). Based upon a combined examination of the available data, we concluded that there are at least 15 confirmed genes (e.g., ESR1, LRP5, SOST, OPG, RANK and RANKL) and potentially another 30 genes or more that could be assigned as osteoporosis susceptibility genes. Notably, these genes are clustered into three biological pathways: the estrogen endocrine pathway, the Wnt/β-catenin signaling pathway and the RANK/RANKL/osteoprotegerin (OPG) pathway.^[4] Since the publication of our review, GWASs have identified two novel osteoporosis genes, ALDH7A1^[5] and JAG1;^[6] two further comprehensive reviews on the genetics of osteoporosis have also been published.^[7,8]

As we highlighted previously, the ultimate promise of osteoporosis genetics is not only to better define the disease process, but more importantly, to lead to better preventive and therapeutic interventions.^[4] Indeed, with rapid advances in next-generation sequencing techniques,^[9,10] we are at a turning point in medical genetics. Notably, whole-genome sequencing has the potential to identify all disease-associated variants, particularly those rare variants that confer a major effect on phenotype expression; rare variants are of paramount relevance for personalized medicine, but so far they have often been overlooked by genotype-based analyses.^[11] In this regard, it is worth emphasizing a specific point. At present, neither of the two direct-to-consumer companies – 23andMe (CA, USA)^[201] and Navigenics (CA, USA)^[202] – test risk markers for osteoporosis, apparently this is because the currently recognized osteoporosis-associated variants are almost invariably common polymorphisms with a modest effect.^[4]

It is hoped that a catalogue of most disease-associated DNA variants for the best-studied complex conditions, such as cardiovascular disease, diabetes and autism, will be available in the next decade.^[12] We hope this might also be the case for osteoporosis, given the continuing efforts of many dedicated researchers around the world. With this in mind, we shall discuss the potential implications of osteoporosis genetics on personalized medicine with a focus on individualized drug therapy. Our basic premises are:

Causative variant(s) with well-defined biological functions will be identified for any single patient in the foreseeable future;
This detailed knowledge of all main risk variants will guide the selective use of medication.

For reasons of simplicity, we shall use findings concerning the aforementioned three biological pathways as examples to illustrate the general principles.

1 2 3 4 5

Next Section

Cite this: Genetics of Osteoporosis: Perspectives for Personalized Medicine - Medscape - Nov 01, 2010.

Table 1. The *ESR1 Pvu*II and *Xba*I polymorphisms and response to estrogen-replacement therapy.
Study	Study population	Study subjects (age in years)	n	Duration of treatment	PvuII genotype^† and response to ERT	XbaI genotype^‡ and response to ERT	Ref.
Han et al.	Korean	Healthy postmenopausal women (41–68)	248	1 year	No association	No association	^[26]
Deng et al.	American	Healthy postmenopausal women (65–87)	54	3.5 years	The pp genotype is associated with a larger increase in bone mass	The XX genotype is associated with a larger increase in bone mass	[27]
Ongphiphadhanakul et al.	Thai	Postmenopausal women with osteoporosis	124	1 year	Women with a P allele had significantly higher increase in vertebral BMD	Not analyzed	[28]
Salmen et al.	Finnish	Healthy perimenopausal women (47–56)	151	5 years	The pp genotype is relatively insensitive to ERT	Not analyzed	[29]
Rapuri et al.	American	Postmenopausal women (65–77)	79	3 years	Women with the PP genotype showed a better response to ERT	Women with the XX genotype showed a better response to ERT	[30]

^† P and p indicate the absence and presence of the PvuII restriction site.
^‡ X indicates the absence of the XbaI restriction site.
ERT: Estrogen-replacement therapy.

Table 2. Predicted functional effect of all the *LRP5* missense mutations reported in the Saarinen study.
Missense mutations	Frequency in fracture-prone children	Frequency in controls	SIFT score	Predicted effect^†
T173M	1/66 (1.5%)	0/235 (0%)	0.01	Deleterious
A422S	1/66 (1.5%)	1/235 (0.4%)	0.00	Deleterious
V667M	3/66 (4.5%)	6/235 (2.6%)	0.00	Deleterious
A1330V	7/66 (10.6%)	20/235 (8.5%)	1.00	Tolerated
G1469R	2/66 (3.0%)	0/235 (0%)	0.02	Deleterious
A1525V	1/66 (1.5%)	3/235 (1.3%)	0.08	Tolerated

^†A SIFT score of ≤0.05 is considered to be deleterious.
SIFT: Sorting intolerant from tolerant.
Data from taken [69].

Sidebar

Executive Summary

Osteoporosis is the most common metabolic bone disorder worldwide.
At least 15 confirmed genes and another 30 or more promising candidate genes have recently been identified as osteoporosis susceptibility genes.
The confirmed and promising osteoporosis susceptibility genes are clustered in three biological pathways: the estrogen endocrine pathway, the Wnt/β-catenin signaling pathway, and the RANK/RANKL/osteoprotegerin (OPG) pathway.
Using data pertaining to these three biological pathways as examples, we illustrate possible principles of personalized therapy for osteoporosis.

ESR1 genotype-based therapy

Estrogen-replacement therapy (ERT) represents one of the therapeutic options for osteoporosis in postmenopausal women.
Not all subjects respond to ERT with equal efficiency and some 8% are nonresponders.
Loss-of-function ESR1 alleles not only predispose an individual to osteoporosis but also confer resistance to ERT. This poses a true dilemma for the successful treatment of postmenopausal osteoporosis.
An ESR defect results in decreased bone mass mainly due to increased bone resorption via upregulation of the RANK/RANKL/OPG signaling pathway. Thus, a strategy that functions to reverse bone resorption through downregulating the RANK/RANKL/OPG signaling pathway in ERT nonresponders is suggested.

RANK/RANKL/OPG genotype-based therapy

The RANK/RANKL/OPG signaling pathway is essential for oesteoclastogenesis. Signaling is initiated by the binding of RANKL to RANK but is inhibited by the binding of OPG to RANKL.
The implication of RANK , RANKL , and OPG genes in both rare human skeletal diseases and common osteoporosis indicates that inhibiting RANK/RANKL/OPG signaling in osteoporosis patients with a predisposing variant(s) in these genes should represent an ideal option for personalized therapy.
A 3-year Phase III study showed that the subcutaneous injection of denosumab 60 mg (a human monoclonal IgG ₂ antibody that binds selectively to RANKL with high affinity and mimics the effect of OPG) every 6 months resulted in reduced risk of fracture in all skeletal sites.

LRP5 genotype-based therapy

The Wnt/β-catenin signaling pathway plays an important role in bone formation. Signaling is initiated by the binding of Wnt to a Frizzled receptor as well as a low-density lipoprotein receptor-related protein (LRP) coreceptor (e.g., LRP5) but is inhibited by the binding of sclerostin (SOST) to LRP5.
Both LRP5 and SOST genes are confirmed osteoporosis genes.
Experiments performed in rodent and primate models and preliminary results obtained from human studies demonstrate the feasibility of SOST inhibition for the personalized treatment of osteoporosis.
Recent experiments performed in mice revealed that the Lrp5 effect on bone formation occurs via gut-derived serotonin. If this finding to be extrapolated to humans, inhibition of the gut-derived serotonin synthesis might suggest a new venue for personalized therapy; osteoporosis patients with a LRP5 defect may be specifically treated by inhibitors of gut-derived serotonin synthesis.

Conclusion & future perspective

Based upon knowledge pertaining to several well-established osteoporosis genes, we discussed principles of individualized therapy in accordance with a patient's genotype.
In particular, we proposed to use inhibitors of the RANK/RANKL/OPG signaling pathway to circumvent resistance to ERT. This novel idea derives from a consideration of the mechanistic link between the estrogen endocrine pathway and the RANK/RANKL/OPG signaling pathway.
In the foreseeable future, physicians should be able to choose the most efficient and effective drugs in accordance with a patient's mutome.
We call for more attention to be focused on rare variants of major effects in future studies.

Comments

Commenting is limited to medical professionals. To comment please Log-in.

Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.